Surface enhanced Raman spectroscopy based analysis of SARS-CoV-2 spike protein binding to ACE2 receptor

The SARS-CoV-2 virus is still a challenge because of its diversity and mutations. The binding interactions of the angiotensin converting enzyme 2 (ACE2) receptor and the spike protein are relevant for the SARS-CoV-2 virus to enter the cell. Consequently, it is important and helpful to analyze binding activities and the changes in the structure of the ACE2 receptor and the spike protein. Surface enhanced Raman spectroscopy is able to analyze small concentrations of the proteins without contact, non-invasively and label-free. In this work, we present a SERS based approach in the visible wavelength range to analyze and study the binding interactions of the ACE2 receptor and the spike protein. SERS measurements of the ACE2 receptor, the spike protein and the ACE2-spike complex were performed. Additionally, an inhibitor was used to prevent the spike protein from binding to ACE2 and to compare the results. The analysis of the measured SERS spectra reveals structural differences and changes due to binding activities. Thus, we show that the performed SERS based approach can help for rapid and non-invasive analysis of binding interactions of the ACE2-spike complex and also of protein binding in general. © 2023 SPIE.

An overview of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2): Pathophysiology, diagnosis, and management tactics

The World Health Organization (WHO) declared an international public health concern on January 30, 2020, in response to the idiopathic Coronavirus disease 2019 (COVID-19) pandemic outbreak. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of the disease being identified as the third human Coronavirus, was discovered in Wuhan, Hubei Province, China. Coronavirus belongs to the Coronaviridae family, Coronavirinae subfamily which according to their genetic structures, are grouped into alphaCoronavirus (aCoV), betaCoronavirus (bCoV), gamma Corona¬virus (yCoV) and deltaCoronavirus (dCoV) of order Nidovirales. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses invading a wide variety of host species. SARS-CoV-2 belongs to extensively. Angiotensin¬converting enzyme 2 (ACE2) is imperative for Novel SARS-CoV-2 to enter host cells as a substrate receptor. With a high mortality rate in the elderly, immune-compromised, diabetic, and patients with cardiovascular and respiratory diseases, COVID-19 is an extremely contagious disease. Patients who are afflicted experience fever, a nonproductive cough, lethargy, dyspnea, and occasionally diarrhoea as well as radiographic signs of pneumonia. A cytokine storm is a result of the immune system's aggressive response to a virus that has propagated inside the body. Genetic recombination and mutation are the main drivers of the emergence of novel SARS-CoV-2 variants. Variants of concern (VOCs) are used to describe some variants having significant virulence and transmission rates, such as the Omicron variants now. RT-LAMP, RT- qPCR, and High-Resolution Computed Tomography, among other new cutting-edge techniques, are effective at diagnosing SARS-CoV-2 infected patients. Standard treatments involving compounds like Lopinavir/Ritonavir, paxlovid, and molnupiravir have shown to be efficacious to some extent against even the newly emerging strains when it comes to treatment approaches. Additionally, immunization is a crucial strategy for preventing the disease or lessening its impact. Live attenuated vaccines, DNA- and RNA-based vaccines, protein subunit vaccines, and amplifying viral vector vaccines are among the molecular frameworks used in the production of vaccines against SARS-CoV-2. Comirnaty by Pfizer-BioNTech, SpikeVax by Moderna, and Vaxzevria by Oxford- AstraZeneca are three extensively incorporated and validated COVID-19 vaccines. In a similar vein, a variety of vaccinations have been created with varying degrees of potency against VOCs. Nanotechnology and artificial intelligence (AI) advancements may help in the provision of an effective and dependable remedy for the eradication of SARS-CoV-2. Definitive diagnosis, community engagements, and united scientific approaches have effectively addressed public health issues amid the pandemic. Although COVID-19 has presented a significant challenge to the healthcare system, it has also provided a chance for the development of novel and creative roles that could have significant effects on the healthcare system. This pandemic has highlighted the value of prompt diagnosis, the value of universal healthcare as well as the need for cutting-edge methods to contain pandemics around the world. © 2023 Nova Science Publishers, Inc. All rights reserved.

Low-level laser therapy for treatment of severe acute respiratory syndrome 2 infection

SARS-CoV-2 is a new threat to public health due to its increased transmissibility and immune evasion. Angiotensin-converting enzyme 2 (ACE2) plays a critical role in SARS-CoV-2 infection as its serve as the virus's major entry receptor in humans. Vaccines have been authorized for emergency use to control the current pandemic and they have greatly reduced the spread of SARS-CoV-2 and mortality rates, nevertheless this coronavirus has shown the ability to endure crucial mutations that increases its infectivity which makes it likely that the virus will continue to mutate and disseminate. There is a need to find and introduce alternative and effective methods of controlling SARS-CoV-2. Notably, low-level laser therapy (LLLT) is a method of exposing cells or tissue to low levels of red and near infrared light which has a high success rate for treatment of other ailments. The aim of the study is to determine for the first time, the effects of LLLT on SARS-CoV-2 infected HEK293/ACE2 cells and compare them to uninfected ones. Both infected and uninfected HEK293/ACE2 cells were irradiated at a wavelength of 640 nm, at different doses. Then, the effects of laser irradiation on the cells and the virus were evaluated using luciferase, cytotoxicity, and cell viability assays. Preliminary results showed that irradiated uninfected cells had no changes in cell viability and cytotoxicity, while there were changes in irradiated infected cells. In addition, laser irradiation caused cell membrane damage in infected cells. Lastly, uninfected irradiated cells showed no luciferase activity while laser irradiation reduced luciferase activity in infected cells. © 2023 SPIE.

Research on the 6XS6 of the SARS-CoV-2 Spike Protein

The 6XS6 is the structure of the SARS-CoV-2 spike protein. The physiological role of the spike protein is relative to the respiratory syndrome coronavirus and has a stronger infect on the human body than the ancestor virus. The purification of the 6XS6 is in the homo sapiens cell by the affinity chromatography, PBS supplemented and Size Exclusion chromatography. At last, using the Cryo-Electron Microscopy to see the structure. This paper is using the D614G mutation to illustrate the structure of the 6XS6. The N-terminal domain and C-terminal domain of the 6XS6 protein are ALA27 and VAL1137. Furthermore, the mutation doesn't have the hydrogen bond because the Asp614 is substituted by the Gly614, and the molecule that interacts with the Ala 647 may occur. While the 6XS6 structure has lots of non-covalent and disulfide bonds. Comparing the structure of the 6XS6 and 6VXX, both are glycoproteins, have three monomers, have two subunits, and have the same category of expression and classification. The different conformations of the two structures can affect the binding ability with the ACE2. This paper can help the researchers to further understand the structure and function of the 6XS6 which can be used in future experiments. © 2023 SPIE.

Immunogenetic landscape of COVID-19 infections related neurological complications

The human leukocyte antigen (HLA) is a critical component of antigen presentation and plays crucial role in conferring differential susceptibility and severity of diseases caused by viruses such as COVID-19. The immunogenetic profile of populations, BCG vaccination status, and a host of lifestyle factors might contribute to the observed variations in mortality rates due to COVID-19. These genetic, epigenetic, and environmental factors could widely influence infection dynamics and immune responses against COVID-19. The aim of this review is to provide an update on HLA association with SARS-CoV-2 infection in global populations and to highlight the possible neurological involvements. We also set out to explore the HLA immunogenetic markers related to COVID‐19 infections that can be used in screening high‐risk individuals for personalized therapies and in community-based vaccine development. © 2023 Elsevier Inc. All rights reserved.

Pericytes may facilitate SARS-CoV-2 entry into the nervous system

Objective: Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified, the neurotropic properties of the causative virus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), remain unknown. We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system, olfactory system, and respiratory system. Method(s): We collected single-cell RNA data from normal brain and nasal epithelium specimens, along with bronchial, tracheal, and lung specimens in public datasets. The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry. We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2 (ACE2) and the spike protein priming enzyme transmembrane serine protease (TMPRSS)/cathepsin L among the specimens. Result(s): The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry. In the nasal epithelium, ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS. Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS. However, coexpression was present in ciliated cells, vascular smooth muscle cells, and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells, AT2 cells, and ciliated cells in lung tissue. Conclusion(s): Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes. Additionally, SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.Copyright © Wolters Kluwer Health, Inc. All rights reserved.

In silico Screening of the Potential Anti-SARS-CoV-2 Activities of Peptides from Vipera ammodytes ammodytes Venom by Molecular Docking

The coronavirus disease 2019 (COVID-19) is induced by the SARS-CoV-2 virus, which caused the global pandemic, infecting approximately 608.328.548 confirmed cases and bringing about 6.501.469 deaths worldwide, as WHO stated in September 2022. The disease is more deadly due to the lack of specific drug molecules or a treatment plan. Therefore, the development of potent pharmacological compounds is urgently required to combat COVID-19. Due to their biological actions, snake venoms constitute a source of potentially beneficial medicinal compounds. Vipera ammodytes ammodytes (VA) is a viper species whose venom has been shown to have anti-proliferative, antimetastatic, anti-cancer, and anti-microbial activities. This in silico study was conducted to evaluate the efficacy of selected VA venom proteins (Adamalysin II, Ammodytoxin A, Ammodytin L, L-amino acid oxidase) against molecular targets;Main protease (3CLpro) and Angiotensin-Converting Enzyme 2 (ACE2) by molecular docking study. Molecular docking investigations were performed by using AutoDock Vina software. All compounds displayed negative binding energy values to 3CLpro and ACE2, suggesting that their interactions with the active sites were favourable. L-amino acid oxidase had the highest binding affinity with both 3CLpro and ACE2. This study revealed for the first time that VA venom proteins are functional inhibitors of 3CLpro and ACE2 activities, and the components of VA venom can be considered potential SARS-CoV-2 inhibitors. However, more studies are needed to validate these compounds in vitro and in vivo. [ FROM AUTHOR] Copyright of Journal of the Institute of Science & Technology / Fen Bilimleri Estitüsü Dergisi is the property of Igdir University, Institute of Science & Technology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Non-steroidal anti-inflammatory drugs amid COVID-19 pandemic: An ally or an enemy?

As the current global pandemic of the novel coronavirus diseases 2019 (COVID-19) continues to rage, the scientific and medical worlds are working to establish an effective therapy against the illness. Recently questions regarding non-steroidal anti-inflammatory drugs (NSAIDs) as a potential therapeutic option for COVID-19 have surfaced. While some studies hint towards the possible benefit of NSAIDs against SARS-CoV-2 infection, the current body of evidence also sheds light on the potential risk of using NSAIDs in COVID-19 patients. Thus, the available literature does not provide conclusive evidence for or against the use of NSAIDs for treating COVID-19 patients. Given the limited data available, we suggest cautionary approaches for the public to avoid possible harm until further evidence emerges. NSAIDs should not be used as the first-line agents for COVID-19 unlessunder medical supervision. Moreover, patients with chronic inflammatory conditions should continue the NSAIDs as per their regular prescriptions.

Mechanisms and implications of COVID-19 transport into neural tissue

The neuropathogenicity of COVID-19 was reported shortly after detection of the virus when patients began reporting symptoms of diminished taste and smell, headaches, mental status changes, and more. As the virus spread, increasing data on viral symptoms in conjunction with novel theories on COVID-19 virulence factors indicated that the virus had neurotropic properties. Several mechanisms have been proposed detailing severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2) transport past the blood–brain barrier and into neural tissue. This chapter offers a comprehensive review of possible neurotropic mechanisms including transport via the angiotensin-converting enzyme 2 (ACE-2) receptor, transportation directly past or through the blood–brain barrier, transsynaptic neuronal transfer, and olfactory conduction. © 2023 Elsevier Inc. All rights reserved.

SARS-CoV-2 Invasion and Pathogenesis of COVID-19: A Perspective of Viral Receptors, Bradykinin, and Purinergic System

The present chapter focuses on the mechanisms of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, pathogenesis, and the possible therapeutic strategies targeted to the viral receptors, purinergic and kallikrein-kinin systems. SARS-CoV-2 spike protein binds with high affinity to the human ACE2 receptor on host cells, but it can also interact with other receptors and enzymes. Following viral infection, a plethora of subsequent molecular and cellular alterations occurs in the host. These alterations, which include the cytokine and bradykinin storms, as well as exacerbated ATP signalling, have been implicated in the genesis and progression of the signs and symptoms observed in COVID-19 patients. These routes and systems provide important targets for developing specific and effective anti-COVID-19 drugs, as well as reveal a novel understanding of pathogenesis and tropism of SARS-CoV-2. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

The Correlation of Single Nucleotide Polymorphism of the ACE2 rs4646116 Gene with The Severity of COVID-19

SUMMARY. Different genetic and immunological factors can affect the severity of Coronavirus disease 19. Angiotensin-converting enzyme 2 is a human receptor for Severe Acute Respiratory Syndrome Coro-navirus-2, and the successful interaction between the spike protein of the novel virus and Angiotensin-converting enzyme 2 is responsible for the initial and complete infection. The study aimed to evaluate the correlation between Single Nucleotide Polymorphisms of Angiotensin converting-enzyme 2, with disease severity of Coronavirus disease 19 in AL-Najaf province. The allele Specific-polymerase Chain reaction method was used for investigating Single Nucleotide polymorphisms of Angiotensin converting-enzyme 2 rs4646116 A/G in different states of Coronavirus disease 19 (COVID-19). The wild genotypes (GG) for ACE2 rs4646116 gene recorded a highly significant association p = 0.0009, and a high ratio in the control group (90%) in comparison with moderate cases of COVID-19 (60%). While the heterozygote genotype (GA) of the same gene showed a significant (p-value = 0.0144) and high ratio in moderate cases (30%) in comparison with the control group (10%). Conclusion(s): the wild genotype (GG) for Angiotensin convert-ing-enzyme 2 rs4646116 gene may be associated with more protection from infection with COVID-19. While the polymorphism heterozygote genotype (GA) for the same gene may be associated with more susceptibility to infection with COVID-19.Copyright © 2023, Colegio de Farmaceuticos de la Provincia de Buenos Aires. All rights reserved.

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

Dihydroisocoumarins of Hydrangea macrophylla var. thunbergia inhibit binding of the SARS-CoV-2 spike protein to ACE2.

Binding of the spike protein of severe acute respiratory syndrome coronavirus 2 to the cognate angiotensin-converting enzyme 2 receptor is the initial step in the viral infection process. In this study, we screened an in-house extract library to identify food materials with inhibitory activity against this binding using enzyme-linked immunosorbent assays and attempted to ascertain their active constituents. Hydrangea macrophylla var. thunbergia leaves were identified as candidate materials. Its active compounds were purified using conventional chromatographic methods and identified as naringenin, dihydroisocoumarins, hydrangenol, and phyllodulcin, which have affinities for angiotensin-converting enzyme 2 receptor and inhibit angiotensin-converting enzyme 2 receptor-spike S1 binding. Given that boiled water extracts of H. macrophylla leaves are commonly consumed as sweet tea in Japan, we speculated that this tea could be used as a potential natural resource to reduce the risk of severe acute respiratory syndrome coronavirus 2 infection.

Multivalent IgM scaffold enhances the therapeutic potential of variant-agnostic ACE2 decoys against SARS-CoV-2.

As immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes.

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling a balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility.

Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of Chymase, Tryptase, and IL-1ß from Human Mast Cells, Augmented by IL-33.

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially in the lungs, leading to what is known as COVID-19. However, the cell source and the mechanism of secretion of such cytokines have not been adequately characterized. In this study, we used human cultured mast cells that are plentiful in the lungs and showed that recombinant SARS-CoV-2 full-length S protein (1-10 ng/mL), but not its receptor-binding domain (RBD), stimulates the secretion of the proinflammatory cytokine interleukin-1ß (IL-1ß) as well as the proteolytic enzymes chymase and tryptase. The secretion of IL-1ß, chymase, and tryptase is augmented by the co-administration of interleukin-33 (IL-33) (30 ng/mL). This effect is mediated via toll-like receptor 4 (TLR4) for IL-1ß and via ACE2 for chymase and tryptase. These results provide evidence that the SARS-CoV-2 S protein contributes to inflammation by stimulating mast cells through different receptors and could lead to new targeted treatment approaches.

Vectored immunoprophylaxis and treatment of SARS-CoV-2 infection in a preclinical model.

Vectored immunoprophylaxis was first developed as a means of establishing engineered immunity to HIV using an adenoassociated viral vector expressing a broadly neutralizing antibody. We applied this concept to establish long-term prophylaxis against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a mouse model using adenoassociated virus and lentiviral vectors expressing a high-affinity angiotensin-converting enzyme 2 (ACE2) decoy. Administration of decoy-expressing (adenoassociated virus) AAV2.retro and AAV6.2 vectors by intranasal instillation or intramuscular injection protected mice against high-titered SARS-CoV-2 infection. AAV and lentiviral vectored immunoprophylaxis was durable and was active against SARS-CoV-2 Omicron subvariants. The AAV vectors were also effective therapeutically when administered postinfection. Vectored immunoprophylaxis could be of value for immunocompromised individuals for whom vaccination is not practical and as a means to rapidly establish protection from infection. Unlike monoclonal antibody therapy, the approach is expected to remain active despite continued evolution viral variants.

Angiotensin-converting enzyme 2 (ACE2) polymorphisms and susceptibility of severe SARS-CoV-2 in a subset of Pakistani population.

Science is digging for the varied presentation of COVID-19 patients exposed to the same risk factors, and medical conditions may be influenced by the presence of polymorphic genetic variants. This study investigated the link between ACE2 gene polymorphisms and the severity of SARS-CoV-2. This cross-sectional study recruited COVID-19 PCR-positive patients by consecutive sampling from Ziauddin Hospital from April to September 2020. DNA was extracted from whole blood, followed by gene amplification and Sanger's sequencing. Most of the patients, 77: 53.8%, were serious. Males were higher (80; 55.9%) with age more than 50 years (106: 74.1%). We found 22 ACE2 SNPs. rs2285666 SNP was most prevalent with 49.2% CC, 45.2% TT, 4.8% CT heterozygosity, and 0.8% AA genotypes. Variants with multiple genotypes were also insignificantly associated with the severity of COVID-19 in the analysis of the dominant model. Only rs2285666 had a significant statistical link with gender (p-value 0.034, OR; 1.438, CI; 1.028-2.011) while rs768883316 with age groups (p-value 0.026, OR; 1.953, CI; 1.085-3.514). Haplotypes ATC of three polymorphisms (rs560997634, rs201159862, and rs751170930) commonly found in 120 (69.77%) and TTTGTAGTTAGTA haplotype consisting of 13 polymorphisms (rs756737634, rs146991645, rs1601703288, rs1927830489, rs1927831624, rs764947941, rs752242172, rs73195521, rs781378335, rs756597390, rs780478736, rs148006212, rs768583671) in 112 (90.32%) had statistically significant association with the severity having p = value 0.029 and 0.001 respectively. Males of old age and diabetics are found to have more severe COVID-19 infection in the current study. We also found that common ACE2 polymorphism rs2285666 influences the susceptibility of acquiring the severe SARS-CoV-2 infection.

Identification of Cyanobacteria-Based Natural Inhibitors Against SARS-CoV-2 Druggable Target ACE2 Using Molecular Docking Study, ADME and Toxicity Analysis.

In 2019-2020, the novel "severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)" had emerged as the biggest challenge for humanity, causing "coronavirus disease 19 (COVID-19)". Scientists around the world have been putting continuous efforts to unfold potential inhibitors of SARS-CoV-2. We have performed computational studies that help us to identify cyanobacterial photoprotective compounds as potential inhibitors against SARS-CoV-2 druggable target human angiotensin-converting enzyme (ACE2), which plays a vital role in the attachment and entry of the virus into the cell. Blocking the receptor-binding domain of ACE2 can prevent the access of the virus into the compartment. A molecular docking study was performed between photoprotective compounds mycosporine-like amino acids, scytonemins and ACE2 protein using AutoDock tools. Among sixteen molecularly docked metabolites, seven compounds were selected with binding energy < 6.8 kcal/mol. Afterwards, drug-likeness and toxicity of the top candidate were predicted using Swiss ADME and Pro Tox-II online servers. All top hits show desirable drug-likeness properties, but toxicity pattern analysis discloses the toxic effect of scytonemin and its derivatives, resulting in the elimination from the screening pipeline. Further molecular interaction study of the rest two ligands, mycosporine-glycine-valine and shinorine with ACE2 was performed using PyMol, Biovia Discovery studio and LigPlot+. Lastly biological activity of both the ligands was predicted by using the PASS online server. Combining the docking score and other studied properties, we believe that mycosporine-glycine-valine and shinorine have potential to be potent inhibitors of ACE2 and can be explored further to use against COVID-19.